Arylpyridines are generally used in organic synthesis as intermediates for the preparation of various kinds of compound; of these, 4-(2xe2x80x2-pyridyl)benzaldehyde is a useful intermediate in the preparation of antiviral drugs and, in particular, of HIV protease inhibitors, such as, for example, the azahexane heterocyclic derivatives described in international patent application WO 97/40029, which is incorporated herein by reference; among the antiviral drugs concerned, one of particular interest is, for example, that indicated by the abbreviation BMS-232632 in Drugs of the Future 1999, 24(4):375, the structural formula of which is given below: 
Arylpyridines can be prepared by aryl-aryl cross-coupling reactions (Lohse et al.; Synlett. 1999, Vol. 1; 45-48. Minato et al., Tetrahedron Letters, Vol. 22, no. 52, pp. 5319-5322. 1981. Ei-ichi Negishi et al. Heterocycles 1982, Vol. 18; 117-122), or coupling reactions between two aryl compounds in accordance with the scheme given below:
ArMeX+PyYxe2x86x92ArPy+MeXY
wherein:
Ar represents an aryl compound and Py represents a pyridine compound; Me represents a metal selected from Mg, Zn and Sn, and X represents Br, Cl, I; or, alternatively, Me and X, together, represent B(OH)2 or BR2 (wherein R is an alkyl group); Y represents Br, Cl or I.
In particular, 4-(2xe2x80x2-pyridyl)benzaldehyde is normally prepared starting from 4-bromobenzaldehyde and 2-bromopyridine (Bold et al.; J.Med.Chem. 1998, 41, 3387 and WO 97/40029), according to the scheme given in FIG. 1. 
The method provides for the conversion of 4-bromobenzaldehyde into the corresponding acetal and then into the Grignard reagent BrMgC6H4CH(OR)2 (compound 1). The Grignard reagent is then reacted with 2-bromopyridine (compound 2) in the presence of NiCl2 and 1,3-bis(diphenylphosphine)propane (Inorg. Chem. 1966, 1968) to give, after the conversion of the acetal group into an aldehyde group, by treatment in an acidic aqueous medium, 4-(2xe2x80x2-pyridyl)benzaldehyde (compound 3).
However, that method has disadvantages of not inconsiderable importance, such as the use of a toxic and carcinogenic catalyst such as the nickel salt and, above all, poor reproducibility, which is all the greater the smaller the amount of catalyst employed.
The object of the work which resulted in the present invention was therefore to find a novel and reliable aryl-aryl cross-coupling process based on the use of metals that are both other than nickel and capable of leading to the formation of arylpyridines, and in particular 4-(2xe2x80x2-pyridyl)benzaldehyde, with reproducible and industrially satisfactory yields, even in the presence of very small amounts of catalyst.
It has now been found that a zinc salt can be used in a catalytic amount and in combination with palladium to catalyse efficiently the formation of arylpyridines by aryl-aryl cross-coupling reactions. In particular, as will be seen hereinafter, it has been found that the zinc salt in combination with palladium catalyses with optimum yields, a high level of productivity and, above all, with a high degree of catalyticity the reactions for the synthesis of arylpyridines according to the general scheme given below 
wherein A and B, which are the same or different from one another, represent H; a linear or branched C1-C8 alkyl; an optionally substituted acetal group; an aryl or a benzyl, which are optionally substituted by groups that do not interfere with a Grignard reaction; and X1 and X2, which are the same or different from one another, represent Cl, Br or I.
The subject-matter of the present invention is particularly interesting bearing in mind that coupling reactions catalysed by palladium and mediated by zinc salts have already been described in Jetter et al., SYNTHESIS, June 1998, 829-831. However, in that article the zinc salt was used in amounts of approximately 2 equivalents with final yields of 70-80%; by increasing the concentration of the zinc salt to 3 equivalents it was possible to obtain a substantial increase in the yield which, however, fell by 40% when only one equivalent of the zinc salt was used.
With the present invention, it has, however, surprisingly been found that the use of a catalytic amount of the zinc salt in the presence of a catalytic amount of palladium leads to the formation of arylpyridines with yields ranging from 84 to 99.5%, depending on the conditions, and also to a substantial reduction in the amount of catalyst; in this connection, among other things, it was also observed that, in the presence of a catalytic amount of the zinc salt, the palladium can be used in an amount of up to 1 mole for every 10,000 moles of arylpyridine product, which is undoubtedly surprising bearing in mind that, in the already mentioned WO 97/40029, the catalyticity was approximately 0.6 mole of nickel per 100 moles of bromopyridine. It is important to remember that the extremely high cost of palladium makes its use in an industrial process economically disadvantageous if it is employed in molar ratios with respect to the substrate of from 1:20 to 1:200.
In this connection, it should be noted that the use of catalytic amounts of zinc salts in combination with catalysts based on nickel or palladium had already been described by Miller and Farrell in Tetrahedron Letters, Vol. 39, 1998, 7275-8, and in the corresponding U.S. Pat. No. 5,922,898. However, those documents describe a method which permits the coupling of Grignard compounds with aryl halides containing groups reactive towards the Grignard compounds, such as, for example, esters, ketones and nitrites, the presence of the zinc salt as a co-catalyst in this case makes it possible to avoid the protection and deprotection of the groups reactive towards the Grignard compounds. In the documents in question, the ratio of the catalyst (Pd or Ni) to the aryl halide is normally approximately 1:20 and, in any case, is never less than 1:100; those documents also give examples demonstrating a high degree of inhibition of the coupling reaction in the presence of a molar ratio of 1:1 between the arylmagnesium reagent and ZnCl2. The fairly high yields are also promoted by the presence of electron-attracting groups on the aryl halides, which increases the reactivity thereof in the aryl-aryl cross-coupling reactions (V. V. Grushin, H. Alper Chem. Rev., 1994, 94, 1047-1062).
In contrast, the subject-matter of the present invention is represented by a process for the preparation of arylpyridines in which an arylmagnesium halide is reacted with a halopyridine in the presence of a catalytic amount of a zinc salt and a catalytic amount of palladium, wherein the molar ratio of the palladium to the halopyridine is less than 1:100 and, normally, less than 1:1000.
In order to avoid any undesired secondary reactions, the arylmagnesium halide and the halopyridine should not contain other substituents capable of interfering with the Grignard reaction or, if such substituents are present, they should be in a suitably protected form; any carbonyl groups can be protected, for example, by being converted beforehand into the corresponding acetals.
According to its preferred embodiment, the process according to the present invention can thus he represented in the following scheme. 
wherein: R1, R2 and R3, which are the same or different from one another, represent H; a linear or branched C1-C6 alkyl; an aryl, preferably phenyl, optionally substituted by a linear or branched C1-C6 alkyl; or, alternatively, R1 and R2 represent an optionally cyclic acetal group; and X1 and X2, which are the same or different from one another, represent Cl, Br or I.
In its more preferred embodiment, the process consists (a) in reacting an arylmagnesium halide of formula: 
wherein X1 represents Cl, Br or I; R1 and R2, which are the same or different from one another, represent linear or branched C1-C6 alkyls, preferably methyls, or alternatively, R1 and R2 together represent a single C1-C8 alkyl or alkylene group; R3 represents hydrogen or a linear or branched C1-C6 alkyl or alkylene radical, with a halopyridine of formula: 
wherein X2 represents Cl, Br or I, in the presence of a catalytic amount of palladium and a catalytic amount of a zinc salt, relative to which compound 1 is prerferably used in dynamic deficiency, (and the molar ratio of the palladium to the arylpyridine product being less than 1:100 and, preferably, less than 1:1000); and (b) in transforming the intermediate compound so obtained into the desired compound by converting the acetal group into a carbonyl group. In particular, it is represented by a process for the preparation of 4-(2xe2x80x2-pyridyl)benzaldehyde in which: (a) an arylmagnesium halide of formula: 
wherein X1, R1 and R2 have the meaning given above, is reacted with a halopyridine of formula: 
wherein X2 has the meaning given above, in the presence of a catalytic amount of palladium and a catalytic amount of a zinc salt, relative to which compound 1 is used in dynamic deficiency (maintaining the molar ratios of compounds 1bis to 2bis within the limits indicated above); and (b) the intermediate compound so obtained of formula: 
is transformed into 4-(2xe2x80x2-pyridyl)benzaldehyde by converting the acetal group into a carbonyl group.
For the purposes of the present invention, the expression xe2x80x9ccatalytic amountxe2x80x9d of the zinc salt means from 1 to 50 moles of zinc, preferably from 5 to 35 moles, per 100 moles of halopyridine; the expression xe2x80x9ccatalytic amountxe2x80x9d of palladium, however, means from 0.01 to 1 mole of palladium, preferably from 0.05 to 0.1 mole, per 100 moles of halopyridine; the expression xe2x80x9cthe Grignard compound is used in dynamic deficiency relative to the zinc saltxe2x80x9d means that the arylmagnesium halide is added dropwise to a solution already containing the halopyridine, the palladium and the zinc salt. Finally, the term xe2x80x9ccatalyticityxe2x80x9d means the molar ratio of the catalyst to the halopyridine; owing to the fact that the process according to present invention results in an almost quantitative conversion of the halopyridine into the arylpyridine product, the xe2x80x9ccatalyticityxe2x80x9d in practice coincides with the molar ratio of the catalyst to the arylpyridine product.
Both in its general version and in its preferred version or in its more preferred version, the molar ratio of the palladium to the halopyridine is normally from 1:3000 to 1:1000, preferably approximately 1:2000; the halopyridine is normally used in amounts of from 0.5 to 1.5 moles, preferably from 0.8 to 1.2 moles, per mole of arylmagnesium halide.
In order for the coupling reaction to take place with high yields and a high degree of selectivity in the presence of a minimum amount of catalyst, the Grignard reagent must be prevented from accumulating in the reaction medium, and must thus be in dynamic deficiency relative to the zinc salt; the amount of co-catalyst (Zn salts) necessary depends on the regularity and the speed of addition of the Grignard compound: a ratio of from 1:50 to 1:10 of the Zn salts to the halopyridine has been found to be satisfactory.
The zinc salt is generally selected from zinc chloride (ZnCl2), zinc bromide (ZnBr2) and zinc acetate [Zn(OAc)2]. However, the palladium is used principally in the form of palladium tetrakistriphenylphosphine [Pd(PPh3)4] or palladium salts, generally acetate or chloride, and phosphines. The phosphines which can be used for this purpose are well known in the art; it is preferable to use unsubstituted phosphines, such as triphenylphosphine, or, alternatively, substituted phosphines, such as tolyl phosphines. The ratio of the palladium to the phosphines is normally one mole of palladium salt per 3-5 moles of phosphines. This reaction can also be carried out in the presence of bidentate ligands, such as, for example, bidentate phosphines, such as 1,3-bis(diphenylphosphine)propane (dppp) or 1,4-bis(diphenylphosphine)butane (dppb); the use of those ligands, in combination with palladium and the zinc salt, makes it possible to obtain molar yields higher than 97% (calculated on the halopyridine) and a catalyticity higher than 2000, using both bromopyridines and the more economical and normally less reactive chloropyridines.
The coupling reaction is generally carried out at a temperature of 25-85xc2x0 C., preferably at 25-50xc2x0 C., in an aprotic organic solvent that does not react with a Grignard compound, preferably in tetrahydrofuran and/or toluene.
In the more preferred embodiment of the invention, the removal of the acetal group is effected by acid hydrolysis; that is to say, stage (b) is normally carried out by treating the intermediate (for example 3bis) with an acidic aqueous solution; this stage is preferably carried out by adding an aqueous HCl solution directly to the organic solution obtained in stage (a) and by maintaining the temperature below 40xc2x0 C.
It is also observed that, when the acetal group of compound 1 is obtained by reacting the corresponding carbonyl group with a C1-C8 diol (preferably with 1,3-propanediol, 1,2-butanediol, 1,4-butenediol or 2,2-dimethyl-1,3-propanediol), the reaction proceeds without the occurrence of secondary reactions or, at any rate, with the formation of undesired secondary products being reduced to a minimum. A further subject of the present invention is therefore represented by a compound of the general formula 
and, preferably, by a compound of formula 
wherein R represents precisely a linear or branched C1-C8 alkyl or alkenyl radical; the preferred radicals are: 1,3-propyl, 1,2-butyl, 1,4-butenyl or 2,2-dimethyl-1,3-propyl.
Finally, as will be seen from the Examples, 4-(2xe2x80x2-pyridyl)benzaldehyde can be used for the preparation of N-1-(tert-butoxycarbonyl)-N-2-[4-(2-pyridyl)-benzyl]-hydrazine and N-1-(tert-butoxycarbonyl)-N-2-{4-[(2-pyridyl)-phenyl]methyl-idene}-hydrazone, which are more advanced intermediates which can likewise be used in the synthesis of the HIV protease inhibitors described above; further subjects of the invention are therefore represented by the procedures for the synthesis of these compounds which comprise a process for the preparation of 4-(2xe2x80x2-pyridyl)benzaldehyde according to the present invention.
In conclusion, the process according to the present invention permits the synthesis of arylpyridines, and in particular of 4-(2xe2x80x2-pyridyl)benzaldehydes, with particularly high, reproducible and industrially satisfactory yields; with a high level of productivity, with a substantially lower use of palladium compared with that described in the prior art for similar reactions, which is particularly important from the point of view of the economical nature of the process, given the extremely high cost of palladium; without the presence of electron-attracting groups on the aryl halides. These and other aspects of the invention will become clear from the following Examples which are to be regarded as non-limiting illustrations thereof.